EP0638119B1 - Chimäre rezeptorgene und entsprechend damit transformierte zellen - Google Patents

Chimäre rezeptorgene und entsprechend damit transformierte zellen Download PDF

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EP0638119B1
EP0638119B1 EP93908414A EP93908414A EP0638119B1 EP 0638119 B1 EP0638119 B1 EP 0638119B1 EP 93908414 A EP93908414 A EP 93908414A EP 93908414 A EP93908414 A EP 93908414A EP 0638119 B1 EP0638119 B1 EP 0638119B1
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cells
receptor
chain
cell
chimeric gene
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EP0638119A4 (de
EP0638119A1 (de
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Zelig Eshhar
Daniel Schindler
Tova Waks
Gideon Gross
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Yeda Research and Development Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/463—Cellular immunotherapy characterised by recombinant expression
    • A61K39/4631—Chimeric Antigen Receptors [CAR]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/4644—Cancer antigens
    • A61K39/464402—Receptors, cell surface antigens or cell surface determinants
    • A61K39/464403—Receptors for growth factors
    • A61K39/464406—Her-2/neu/ErbB2, Her-3/ErbB3 or Her 4/ ErbB4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/42—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins
    • C07K16/4283—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an allotypic or isotypic determinant on Ig
    • C07K16/4291—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an allotypic or isotypic determinant on Ig against IgE
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/44—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material not provided for elsewhere, e.g. haptens, metals, DNA, RNA, amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/7051—T-cell receptor (TcR)-CD3 complex
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment

Definitions

  • the present invention relates to chimeric receptor genes suitable for endowing lymphocytes with antibody-type specificity, to expression vectors comprising said chimeric genes and to lymphocytes transformed with said expression vectors.
  • Various types of lymphocyte cells are suitable, for example, cytotoxic T cells, helper T cells, natural killer (NK) cells, etc.
  • the transformed lymphocytes are useful in therapeutic treatment methods.
  • TCR/CD3 antigen-specific T cell receptor complex
  • TCR T cell receptor for antigen
  • MHC major histocompatibility complex
  • CD3 CD3 is assumed to be responsible for intracellular signalling following occupancy of the TCR by ligand.
  • TCR/CD3 The T cell receptor for antigen-CD3 complex (TCR/CD3) recognizes antigenic peptides that are presented to it by the proteins of the major histocompatibility complex (MHC). Complexes of MHC and peptide are expressed on the surface of antigen presenting cells and other T cell targets. Stimulation of the TCR/CD3 complex results in activation of the T cell and a consequent antigen-specific immune response.
  • the TCR/CD3 complex plays a central role in the effector function and regulation of the immune system.
  • T cell receptor for antigen Two forms of T cell receptor for antigen are expressed on the surface of T cells. These contain either ⁇ / ⁇ heterodimers or ⁇ / ⁇ heterodimers. T cells are capable of rearranging the genes that encode the ⁇ , ⁇ , ⁇ and ⁇ chains of the T cell receptor. T cell receptor gene rearrangements are analogous to those that produce functional immunoglobulins in B cells and the presence of multiple variable and joining regions in the genome allows the generation of T cell receptors with a diverse range of binding specificities. Each ⁇ / ⁇ or ⁇ / ⁇ heterodimer is expressed on the surface of the T cell in association with four invariant peptides. These are the ⁇ , ⁇ and ⁇ subunits of the CD3 complex and the zeta chain.
  • the CD3 ⁇ , ⁇ and ⁇ polypeptides are encoded by three members of the immunoglobulin supergene family and are found in a cluster on human chromosome 11 or murine chromosome 9.
  • the zeta chain gene is found separately from other TCR and CD3 genes on chromosome 1 in both the mouse and human.
  • the CD3 chains and the zeta subunit do not show variability, and are not involved directly in antigen recognition.
  • T cell receptor All the components of the T cell receptor are membrane proteins and consist of a leader sequence, externally-disposed N-terminal extracellular domains, a single membrane-spanning domain, and cytoplasmic tails.
  • the ⁇ , ⁇ , ⁇ and ⁇ antigen-binding polypeptides are glycoproteins.
  • the zeta chain has a relatively short ectodomain of only nine amino acids and a long cytoplasmic tail of approximately 110 amino acids.
  • Most T cell receptor ⁇ / ⁇ heterodimers are covalently linked through disulphide bonds, but many ⁇ ⁇ receptors associate with one another non-covalently.
  • the zeta chain quantitatively forms either disulphide-linked ⁇ - ⁇ heterodimers or zeta-zeta homodimers.
  • Fc receptor Another example of a type of receptor on cells of the immune system is the Fc receptor.
  • effector functions such as antibody-dependent cytotoxicity, mast cell degranulation, and phagocytosis to immunomodulatory signals such as regulating lymphocyte proliferation, phagocytosis and target cell lysis. All these interactions are initiated through the binding of the Fc domain of antibodies or immune complexes to specialized cell surface receptors on hematopoietic cells.
  • FcRs structural heterogeneity of Fc receptors
  • FcRs are defined by their specificity for immunoglobulin isotypes.
  • Fc receptors for IgG are referred to as Fc ⁇ R, for IgE as Fc ⁇ R, for IgA as Fc ⁇ R, etc.
  • Structurally distinct receptors are distinguished by a Roman numeral, based on historical precedent.
  • Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIII Two groups of Fc ⁇ R have been defined; these are referred to as Fc ⁇ RI and Fc ⁇ RII.
  • Structurally related although distinct genes within a group are denoted by A, B, C.
  • the protein subunit is given a Greek letter, such as Fc ⁇ RIIIA ⁇ , Fc ⁇ RIIIA ⁇ .
  • Fc ⁇ R IgG and IgE Fc receptors
  • Fc ⁇ R IgG and IgE Fc receptors
  • Those studies make it apparent that Fc receptors share structurally related ligand binding domains, but differ in their transmembrane and intracellular domains which presumably mediate intracellular signalling.
  • specific Fc ⁇ Rs on different cells mediate different cellular responses upon interaction with an immune complex.
  • the structural analysis of the Fc ⁇ Rs and Fc ⁇ RI has also revealed at least one common subunit among some of these receptors. This common subunit is the ⁇ subunit, which is similar to the ⁇ or ⁇ chain of the TCR/CD3, and is involved in the signal transduction of the Fc ⁇ RIII and Fc ⁇ RI.
  • the low affinity receptor for IgG is composed of the ligand binding CD16 ⁇ (Fc ⁇ RIIIA ⁇ ) polypeptide associated with the ⁇ chain (Fc ⁇ RIIIA ⁇ ).
  • the CD16 polypeptide appears as membrane anchored form in polymorphonuclear cells and as transmembrane form (CD16 TM ) in NK.
  • the Fc ⁇ RIIIA serves as a triggering molecule for NK cells.
  • IL-2 receptor Another type of immune cell receptor is the IL-2 receptor. This receptor is composed of three chains, the ⁇ chain (p55), the ⁇ chain (p75) and the ⁇ chain. When stimulated by IL-2, lymphocytes undergo proliferation and activation.
  • Antigen-specific effector lymphocytes such as tumor specific T cells (Tc) are very rare, individual-specific, limited in their recognition spectrum and difficult to obtain against most malignancies. Antibodies, on the other hand, are readily obtainable, more easily derived, have wider spectrum and are not individual-specific.
  • the major problem of applying specific antibodies for cancer immunotherapy lies in the inability of sufficient amounts of monoclonal antibodies (mAb) to reach large areas within solid tumors. In practice, many clinical attempts to recruit the humoral or cellular arms of the immune system for passive anti-tumor immunotherapy have not fulfilled expectations. While it has been possible to obtain anti-tumor antibodies, their therapeutic use has been limited so far to blood-borne tumors (1, 2) primarily because solid tumors are inaccessible to sufficient amounts of antibodies (3).
  • effector lymphocytes in adoptive immunotherapy, although effective in selected solid tumors, suffers on the other hand, from a lack of specificity (such as in the case of lymphokine-activated killer cells (LAK cells) (4) which are mainly NK cells) or from the difficulty in recruiting tumor-infiltrating lymphocytes (TILs) and expanding such specific T cells for most malignancies (5).
  • LAK cells lymphokine-activated killer cells
  • TILs tumor-infiltrating lymphocytes
  • a strategy which has been recently developed allows one to combine the advantage of the antibody's specificity with the homing, tissue penetration, cytokine production and target-cell destruction of T lymphocytes and to extend, by ex vivo genetic manipulations, the spectrum of anti-tumor specificity of T cells.
  • the laboratory of the present inventors succeeded to functionally express in T cells chimeric T cell receptor (cTCR) genes composed of the variable region domain (Fv) of an antibody molecule and the constant region domain of the antigen-binding TCR chains, i.e., the ⁇ / ⁇ or ⁇ / ⁇ chains.
  • cTCR chimeric T cell receptor
  • genomic expression vectors have been constructed containing the rearranged gene segments coding for the V region domains of the heavy (V H ) and light (V L ) chains of an anti-2,4,6-trinitrophenyl (TNP) antibody (Sp6) spliced to either one of the C-region gene segments of the ⁇ or ⁇ TCR chains.
  • TNP -2,4,6-trinitrophenyl
  • Sp6 anti-2,4,6-trinitrophenyl
  • a functional TCR was detected.
  • the chimeric TCR exhibited the idiotope of the Sp6 anti-TNP antibody and endowed the T cells with a major histocompatibility complex (MHC) non-restricted response to the hapten TNP.
  • MHC major histocompatibility complex
  • the transfectants specifically killed TNP-bearing target cells, and produced interleukin-2 (IL-2) in response thereto across strain and species barriers. Moreover, such transfeccants responded to immobilized TNP-protein conjugates, bypassing the need for cellular processing and presentation.
  • the chimeric TCRs could provide T cells with an antibody-like specificity and, upon encountering antigen, were able to effectively transmit signals for T cell activation, secretion of lymphokines and specific target cell lysis in a MHC nonrestricted manner.
  • the cTCR bearing cells undergo stimulation by immobilized antigen, proving that receptor-mediated T-cell activation is not only nonrestricted but also independent of MHC expression on target cells (8, 9).
  • New expression cassettes were also developed based on reverse transcription of mRNA and PCR amplification of rearranged V H and V L DNA, using primers based on 3' and 5' consensus sequences (12) of these genes which allow rapid construction of cTCR genes from any mAb-producing hybridoma.
  • cTCR genes composed of combining sites of anti-idiotypic antibody specific to the surface IgM of the 38C13 murine B lymphoma cell line.
  • retroviral vectors have been demonstrated to be effective for transgene expression in human T cells (13, 14), due to the fact that two genes have to be introduced in order to express functional cTCR (C ⁇ V H +C ⁇ V L or C ⁇ V L +C ⁇ V H ), and the very low efficiency of transduction of a single cell with two separate retroviral vectors, new vectors have to be tried which will allow the transduction of two genes in tandem (15).
  • Another strategy which has recently been developed employs joining of the extracellular ligand binding domain of receptors such as CD4, CD8, the IL-2 receptor, or CD16, to the cytoplasmic tail of either one of the ⁇ / ⁇ family members (26-28, 38). It has been shown that crosslinking of such extracellular domains through a ligand or antibody results in T cell activation. Chimeric CD4 or CD16- ⁇ / ⁇ molecules expressed in cytotoxic lymphocytes could direct specific cytolysis against appropriate target cells (26; 38).
  • scFv single-chain Fv domain
  • a chimeric gene which combines the antibody recognition site and the lymphocyte-signalling moiety into one continuous chain.
  • c-scFvR chimeric scFv-receptor
  • the present invention thus relates to chimeric genes suitable to endow lymphocyte cells with antibody-type specificity.
  • Various types of lymphocytes are suitable, for example, natural killer cells, helper T cells, suppressor T cells, cytotoxic T cells, lymphokine activated cells, subtypes thereof and any other cell type which can express chimeric receptor chain.
  • the chimeric gene comprises a first gene segment encoding a single-chain Fv domain (scFv) of a specific antibody and a second gene segment, encoding partially or entirely the transmembrane and cytoplasmic, and optionally the extracellular, domains of an immune cell-triggering molecule which, upon transfection to immune cells, expresses both said scFv domain and said domains of said immune cell-triggering molecule in one single chain on the surface of the transfected cells in a manner such that the transfected cells are triggered to activate and/or proliferate and have MHC non-restricted antibody-type specificity when said expressed scFv domain binds to its antigen.
  • scFv single-chain Fv domain
  • the present invention further relates to suitable vectors for transfecting cells of the type defined above with the chimeric gene.
  • the present invention further relates to cells of the type defined above into which such chimeric gene has been introduced so as to obtain its expression, and also to pharmaceutical prophylactic and curative compositions containing an effective quantity of such cells.
  • the present invention relates to a process for the generation of lymphocytes transfected with an expression vector containing a chimeric gene of the invention.
  • a model system which comprises an expression vector which was transfected into cytotoxic T cells and which was functionally expressed in said cells, i.e., which directed the cellular response of the lymphocyte against a predefined target antigen in a MHC nonrestricted manner.
  • the genetically engineered lymphocyte cells of the present invention may be used in new therapeutic treatment processes.
  • T cells or NK cells isolated from a patient may be transfected with DNA encoding a chimeric gene including the variable region of an antibody directed toward a specific antigen, and then returned to the patient so that the cellular response generated by such cells will be triggered by and directed toward the specific antigen in a MHC nonrestricted manner.
  • peripheral blood cells of the patient are genetically engineered according to the invention and then administered to the patient.
  • the present invention allows us to confer antibody specificity using not only the TCR components, but other lymphocyte-signalling chains, such as the zeta/eta chains of CD3, ⁇ chain of the Fc ⁇ R and Fc ⁇ R, ⁇ , ⁇ and ⁇ chains of the IL-2R or any other lymphokine receptor, CD16 ⁇ -chain, CD2, CD28, and others.
  • lymphocyte-signalling chains such as the zeta/eta chains of CD3, ⁇ chain of the Fc ⁇ R and Fc ⁇ R, ⁇ , ⁇ and ⁇ chains of the IL-2R or any other lymphokine receptor, CD16 ⁇ -chain, CD2, CD28, and others.
  • chimeric molecules were constructed composed of the scFv linked to receptor subunits that might serve to transduce the signal from the scFv and confer antibody specificity to T cells as well as other lymphocytes.
  • This construction is preferably accomplished in the manner shown in Fig. 1 at A , DNA or RNA from antibody forming cells is isolated.
  • cDNA is prepared from mRNA and amplification of the antibody light and heavy variable regions (V H and V L ) by PCR using a V L -5' (XbaI), V L -3 (SalI), V H -5' (SalI) and V H -3' (BstEII) specific primers.
  • RNA from T lymphocytes was isolated and from the cDNA prepared the ⁇ , ⁇ chains of the TCR, ⁇ , ⁇ subunits of the CD3, CD16 ⁇ of the FC ⁇ RIII, or IL-2 receptors (commonly denoted here as R) can be amplified using a specific set of primers for each chain. All the primers include a Xbal at their 5' end and a few bases downstream of the XbaI or the BstEII site. At the 3' end, all receptor chains contain a SnaBI site.
  • the receptor was introduced at the XbaI site of the pRSVneoL ⁇ vector obtaining pRSVneoL ⁇ -R.
  • the amplified V L (digested with XBaI-SalI) and V H (digested with SalI-BstEII) regions are introduced into the XbaI-BstEII digested pRSVneoL ⁇ -R plasmid in a three-piece ligation.
  • the resulting plasmid pRSVscFvR contains the complete chimeric single chain receptor.
  • the receptor (R) gene segment described in Figs. 13-18 is the human TCR C ⁇ .
  • the new strategy according to the invention enables the use of other receptor molecules which might serve to transduce the signal from the scFv and confer antibody specificity to T cells as well as other immune cells.
  • it allows the expression of the scFv as the antigen recognition unit of chimeric molecules composed of the transmembrane and cytoplasmic domains of receptor molecules of immune cells, such as T cells and natural killer (NK) cells.
  • NK natural killer
  • Such receptors can be single or multi-chain in nature and not necessarily belong to the Ig gene superfamily.
  • Candidate molecules for this approach are receptor molecules which take part in signal transduction as an essential component of a receptor complex, such as receptors which trigger T cells and NK activation and/or proliferation.
  • Examples of triggers of T cells are subunits of the TCR, such as the ⁇ , ⁇ , ⁇ or ⁇ chain of the TCR, or any of the polypeptides constituting the CD3 complex which are involved in the signal transduction, e.g., the ⁇ , ⁇ , and ⁇ CD3 chains.
  • polypeptides of the TCR/CD3 (the principal triggering receptor complex of T cells), especially promising are the zeta and its eta isoform chain, which appear as either homo- or hetero-S-S-linked dimers, and are responsible for mediating at least a fraction of the cellular activation programs triggered by the TCR recognition of ligand (18, 19).
  • These polypeptides have very short extracellular domains which can serve for the attachment of the scFv.
  • immune cell trigger molecules are any one of the IL-2 receptor (IL-2R) p55 ( ⁇ ) or p75 ( ⁇ ) or ⁇ chains, especially the p75 and ⁇ subunits which are responsible for signaling T cell and NK proliferation.
  • IL-2R IL-2 receptor
  • Further candidate receptor molecules for creation of scFv chimeras in accordance with the present invention include the subunit chains of Fc receptors.
  • NK-stimulatory receptors the most attractive candidates are the ⁇ - and CD16 ⁇ -subunits of the low affinity receptor for IgG, Fc ⁇ RIII. Occupancy or cross-linking of Fc ⁇ RIII (either by anti-CD16 or through immune complexes) activates NK cells for cytokine production, expression of surface molecules and cytolytic activity (20, 21).
  • Fc ⁇ RIII appears as a heterooligomeric complex consisting of a ligand-binding ⁇ chain associated with a disulfide-linked ⁇ or zeta chain.
  • the Fc ⁇ RIIIA signalling gamma chain (22) serves also as part of the Fc ⁇ RI complex, where it appears as a homodimer, is very similar to the CD3 zeta chain, and in fact can form heterodimers with it in some cytolytic T lymphocytes (CTL) and NK cells (23-25).
  • CTL cytolytic T lymphocytes
  • NK cells 23-25.
  • lymphocyte accessory and adhesion molecules such as CD2 and CD28, which transduce a co-stimulatory signal for T-cell activation.
  • co-stimulatory receptors can also be used in accordance with the present invention.
  • the single chain Fv chimeras can be made by joining the scFv domain with any receptor or co-receptor chain having a similar function to the disclosed molecules, e.g., derived from granulocytes, B lymphocytes, mast cells, macrophages, etc.
  • the distinguishing features of desirable immune cell trigger molecules comprise the ability to be expressed autonomously (i.e., as a single chain), the ability to be fused to an extracellular domain such that the resultant chimera is expressed on the surface of an immune cell into which the corresponding gene was genetically introduced, and the ability to take part in signal transduction programs secondary to encounter with a target ligand.
  • the scFv domain must be joined to the immune cell triggering molecule such that the scFv portion will be extracellular when the chimera is expressed. This is accomplished by joining the scFv either to the very end of the transmembrane portion opposite the cytoplasmic domain of the trigger molecule or by using a spacer which is either part of the endogenous extracellular portion of the triggering molecule or from other sources.
  • the chimeric molecules of the present invention have the ability to confer on the immune cells on which they are expressed MHC nonrestricted antibody-type specificity. Thus, a continuous polypeptide of antigen binding and signal transducing properties can be produced and utilized as a targeting receptor on immune cells.
  • the target cells are tumor cells and the scFv domain is derived from an antibody specific to an epitope expressed on the tumor cells. It is expected that such anti-tumor cytolysis can also be independent of exogenous supply of IL-2, thus providing a specific and safer means for adoptive immunotherapy.
  • the immune cells are T-cells or NK-cells.
  • the antibody scFvR design of the present invention will thus involve retargeting lymphocytes in vivo in an MHC-non-restricted manner.
  • the T-cells can be retargeted in vivo to tumor cells or any other target of choice toward which antibodies can be raised.
  • single-chain Fv domain is intended to include not only the conventional single-chain antibodies as described in references 16 and 17, the entire contents of which are hereby incorporated herein by reference, but also any construct which provides the binding domain of an antibody in single-chain form as, for example, which may include only one or more of the complementarity determining regions (CDRs), also known as the hypervariable regions, of an antibody.
  • CDRs complementarity determining regions
  • the gene encoding the transmembrane and cytoplasmic portions of the receptor molecule may correspond exactly to the natural gene or any gene which encodes the protein in its natural amino acid sequence.
  • the present invention comprehends muteins characterized by certain minor modifications to the amino acid structure of the molecule, such that the mutant protein molecules are substantially similar in amino acid sequence and/or 3D structure, and possess a similar biological activity, relative to the native protein.
  • the transformed cells of the present invention may be used for the therapy of a number of diseases.
  • Current methods of administering such transformed cells involve adoptive immunotherapy or cell-transfer therapy. These methods allow the return of the transformed immune system cells to the blood stream. Rosenberg, S.A., Scientific American 62 (May 1990); Rosenberg et al., The New England Journal of Medicine 323(9) :570 (1990).
  • the transformed cells of the present invention may be administered in the form of a pharmaceutical composition with suitable pharmaceutically acceptable excipients. Such compositions may be administered to any animal which may experience the beneficial effects of the transformed cell of the present invention, including humans.
  • the antibodies which are used to make the scFv portion of the present invention may be any antibody, the specificity of which is desired to be transferred to the immune cell.
  • Such antibody may be against tumor cells, cells expressing viral antigens, anti-idiotypic or anti-clonotypic antibodies in order to specifically eliminate certain B-cells and T-cells, or antibodies against the constant region of immunoglobulin determinants.
  • the antibody is specific to the constant portion of IgE, it can serve to eliminate IgE-producing B-cells in order to alleviate allergy, etc.
  • This list of possible antibodies is not intended to be exclusive and those of ordinary skill in the art will be aware of many additional antibodies for which important utilities exist upon combination with the receptor in accordance with the present invention.
  • genes of the present invention can be introduced into the immune cells by any manner known in the art, such as, for example, calcium phosphate transfection, electroporation, lipofection, transduction by retrovirus vector, use of a retroviral vector or a viral vector, etc.
  • the scFvR design is advantageous over the cTCR one. It requires the expression of only one gene instead of the gene pair required for the cTCR, thereby providing simpler construction and transfection.
  • the scFvR design can be employed to confer antibody specificity on a larger spectrum of signaling molecules composed of only one chain. Additionally, the scFv maintains both V H and V L together in one chain; thus, even upon mixed pairing of chimeric with endogenous chains, the antigen-binding properties of the molecule are conserved. Finally, the fact that gamma and zeta constitute the signaling chains of the TCR/CD3, the Fc ⁇ RIII and the Fc ⁇ RI expands the feasibility of exploiting the chimeric receptor for retargeting other hematopoietic cells, such as NK cells, basophils, or mast cells in addition to T cells.
  • This approach exploits the scFv as the antigen-recognition unit and the potent cytotoxic responses of NK cells and T cells and/or the ability of T cells to secrete lymphokines and cytokines upon activation at the target site, thus recruiting, regulating and amplifying other arms of the immune system.
  • the chimeric scFv receptors can confer on the lymphocytes the following functions: antibody-type specificity toward any predefined antigen; specific "homing" to their targets; specific recognition, activation, and execution of effector function as a result of encountering the target; and specific and controlled proliferation at the target site. Endowing the lymphocytes with an Fv from an antibody may also serve for controlled and selective blocking of the aforementioned functions using soluble haptens or Fab' of anti-idiotypic antibodies.
  • NK cells lymphokine-activated killer cells (LAK), cytotoxic T cells, helper T cells, and the various subtypes of the above. These cells can execute their authentic natural function and can serve, in addition, as carriers of foreign genes designated for gene therapy, and the chimeric receptor shall serve in this case to direct the cells to their target.
  • This approach can be applied also to anti-idiotypic vaccination by using helper T cells expressing chimeric receptors made of Fv of antiidiotypic antibodies.
  • helper T cells expressing chimeric receptors made of Fv of antiidiotypic antibodies.
  • Such "designer lymphocytes” will interact and stimulate idiotype-bearing B cells to produce antigen-specific antibodies, thus bypassing the need for active immunization with toxic antigens.
  • the surface expression of the scFvR ⁇ or scFvR ⁇ molecule was independent of the TCR/CD3 complex; it did not restore surface expression of the CD3 in MD45.27J transfected STB or STZ cells, and some subclones of the STA that initially expressed both scFvR ⁇ and TCR/CD3 on their surface lost, upon a prolonged culture period, the TCR/CD3 expression without any apparent effect on the scFvR ⁇ expression and function (not shown).
  • the MD.45 T cell hybridoma can be triggered through its TCR to produce IL-2, IL-3 or GM-CSF. It specifically recognizes and responds to H-2 b target cells (29), while its MD45.27J mutant cannot be stimulated through its TCR due to the absence of an ⁇ chain.
  • H-2 b target cells 29
  • MD45.27J mutant cannot be stimulated through its TCR due to the absence of an ⁇ chain.
  • TNP-F ⁇ G plastic-immobilized TNP-fowl gamma globulin
  • Fig. 6B plastic-immobilized TNP-fowl gamma globulin
  • Non-modified A.20 cells or F ⁇ G did not activate the transfectants, demonstrating the specificity of the response toward TNP.
  • Stimulation of the various transfectants with immobilized antigen resulted in different degrees of reactivity.
  • STA responded to plastic-bound TNP-F ⁇ G in consistent manner, STB and STZ (transfected with the scFvR ⁇ and scFvR ⁇ , respectively) lost their ability to undergo stimulation with immobilized antigen but not with hapten-modified cells. Such behavior suggests the necessity of additional synergistic signals for these cells.
  • a single-chain Fv of an antibody molecule fused to the gamma chain of the immunoglobulin Fc receptor or to the zeta chain of the CD3 complex can be expressed in T cells as an antigen-specific receptor.
  • the demonstration that the scFvR ⁇ / ⁇ fusion protein could mediate antigen-specific stimulation of T cells not expressing the TCR/CD3 receptor complex (as shown for the STB and STZ transfectants derived from the TCR-negative MD.27J mutant (Figs.
  • chimeric CD4 or CD16-gamma/zeta molecules expressed in cytotoxic lymphocytes could direct specific cytolysis against appropriate target cells (26, 38).
  • the Neu/HER2 (also called c-erbB- 2) is a protooncogene product that encodes a growth factor receptor implicated in the malignancy of several human adenocarcinomas that overexpress it.
  • mAbs monoclonal antibodies specific to the extracellular portion of the Neu/HER2 protein (41)
  • mAb N29 which significantly inhibited the tumorigenic growth of HER2/ Neu transfected fibroblasts in nude mice, and induced phenotypic differentiation of various cultured breast cell lines (42).
  • T cells equipped with anti-Neu/HER2 specificity as the ligand binding domain of the chimeric receptor respond specifically to Neu/HER2 bearing target cells.
  • the single-chain chimeric receptor was found to transduce specific signals for T cell activation. Incubation of the scFvR-expressing cells together with human cancer cells, which express Neu/HER2 on their surface, resulted in a marked activation as measured by the production of IL-2 (Fig. 10a).
  • This activation was mediated by the scFvR and was Neu/HER2-specific, since cells which do not overexpress Neu/HER2, like MDA-MB468 human breast carcinoma cells, did not stimulate the production of high levels of IL-2, whereas cells that display large amounts of Neu/HER2, like the breast carcinoma SKBR-3 cells, ovarian carcinoma SKOV-3 cells and an erbB -2 transfected murine fibroblast cell line, stimulated the hybridomas to produce high IL-2 levels. Soluble, purified HER2X partially blocked the activation by the breast carcinoma cells. However, upon immobilization, it served as a potent T cell activator, but only for the transfected cells (Fig. 10b). The T cell response to the immobilized antigen was in general weaker than to the cellular targets. Possibly, co-stimulatory signals provided by accessory and adhesion molecules during T cell interactions may amplify the intercellular interaction.
  • the ability of the transfected cells to mediate specific target cell killing was determined by the 51 Cr release assay.
  • a variety of Neu/HER2 expressing cells were tested as targets (Fig. 11)
  • the HER2 cell line, an NIH-3T3 fibroblast overexpressing Neu/HER2 could serve as an adequate target.
  • an scFvR ⁇ -expressing T cell hybridoma N29 ⁇ 1
  • a substantial level of specific lysis was obtained.
  • the scFvR ⁇ expressing hybridoma (N29 ⁇ 18) gave only a marginal specific 51 Cr release signal when compared with the untransfected hybridomas.
  • the cytolytic effect was Neu/HER2-specific, since untransfected NIH-3T3 fibroblasts did not undergo killing. Likewise, the parental MD45.27J cells did not cause any significant 51 Cr release. The high levels of spontaneous 51 Cr release from several candidate human tumor lines that we tested, did not allow us to determine the killing potency in a reproducible manner. Nevertheless, in all experiments, the transfected cells induced a significantly higher specific 51 Cr release from human tumors (such as SKBR-3 breast and N87 gastric carcinoma cell lines, Fig. 11), than the parental hybridomas.
  • Allergic diseases are characterized by elevated synthesis of IgE upon stimulation by environmental allergens.
  • the production of IgE is regulated by antigen specific helper and suppressor T cells.
  • T lymphocytes following activation, induce B cells to produce IgE.
  • the secreted IgE binds preferentially to high affinity Fc ⁇ receptors (Fc ⁇ RI) on mast cells and basophils, thus sensitizing them.
  • Fc ⁇ RI-bound IgE is cross-linked and stimulates exocytosis of granule-associated preformed pharmacologic mediators such as histamine. Elimination of IgE producing cells can therefore terminate IgE production and thus prevent the onset of allergic responses.
  • scFvC ⁇ can arm and trigger cytotoxic cells to eliminate IgE producing cells (known to express IgE on their surface).
  • IgE producing cells known to express IgE on their surface.
  • target cells murine splenic lymphocytes which were induced to produce IgE by culturing them in the presence of lipopolysaccharide (LPS) and IL-4.
  • LPS+IL-4 are known to induce Ig class switch in B cells and specifically trigger IgE and IgG 1 formation (50).
  • control 84.1c B cell hybridoma to cause such effect demonstrates that the lack of IgE accumulation in the culture medium is not because of passive absorption of IgE by the 84.1c anti-IgE antibodies.
  • This set of experiments clearly demonstrates that cytotoxic T cells equipped with chimeric scFv-TCR can specifically eliminate their target cells.
  • NK natural killer
  • Fc ⁇ RIIIA the low affinity receptor for IgG
  • NK cells Triggering of NK cells via Fc ⁇ RIII (either by anti-CD16 or through immune complexes) includes cytokine production, expression of surface molecules and cytolytic activity (53, 21).
  • the CD16 polypeptide appears as membrane anchored form in polymorphonuclear cells and as transmembrane form (CD16 TM ) in NK (54).
  • the Fc ⁇ RIII-associaced ⁇ chain serves also as part of the Fc ⁇ RI complex where it appears as homodimer, is very similar to the CD3 ⁇ chain and can form heterodimers with it in some CTL and NK cells (52, 21, 28, 23-25).
  • chimeras between ⁇ and CD4 directed CTL to recognize and kill cells expressing the HIV gp120 (26).
  • Similar chimeric receptors between either the extracellular domain of CD8 (27) or Tac (28) in conjunction with ⁇ , ⁇ or ⁇ have been recently reported in studies mapping the regions of these molecules which take part in the signaling process.
  • the Sp6-IL-2-R chimeric gene was prepared by joining DNA containing the scFv of Sp6 to a 936bp DNA segment cloned from PCR amplified DNA (using primers 20 and 23 of Table I) containing the cytoplasmic and transmembrane regions (carboxy 312 amino acids) of the ⁇ -chains of the human IL-2 receptor.
  • Figure 25 shows the results of immunofluorescence staining of one such RBL transf ectant with anti-Sp6 idiotypic antibodies.
  • BW5147 is a murine thymoma cell line which do not express the TCR or Fc ⁇ R complexes (due to a defect in the ⁇ chain transcription (57)), and therefore served as a convenient cell-line to study the expression of the different chimeric scFv receptors. Because BW cells do not produce endogenous ⁇ or ⁇ chains, it is expected that following transfection, the chimeric receptors will be composed only of homodimers of the exogenous transgenes (in the case of scFvR ⁇ or scFvR ⁇ ). Also, it provides a system to study whether the chimeric scFvCD16 can be expressed independently of ⁇ or ⁇ chains.
  • the chimeric genes composed of an scFv of Sp6 anti-TNP mAb joined to either one of the ⁇ , ⁇ or CD16 chains were introduced by electroporation into the BW cells and selected transfectants which grew in the presence of G-418 were analyzed for surface expression of the Sp6 idiotope using the 20.5 anti-Sp6 idiotypic mAb.
  • a group of BW cells was co-transfected with a mixture of scFvCD16+ ⁇ chain DNA.
  • the immunofluorescence pattern of staining analysed by PACS is depicted in Fig. 26.
  • both BW.Sp6- ⁇ and BW.Sp6- ⁇ transfectants (which received weither scFvR ⁇ or scFvR ⁇ DNA, respectively) could be specifically stained with anti-Sp6 idiotypic antibody and thus express a moderate level of the chimeric receptor chains on their surface.
  • anti-CD3 mAb we could not observe any surface staining of the scFvR ⁇ or scFvR ⁇ transfectants (not shown), indicating that these chimeric genes are expressed on the cell surface independently of the CD3 complex. None of the transfectants which was electroporated with scFvCD16 alone did express surface receptor (unshown).

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Claims (25)

  1. Chimeres Gen, umfassend einen ersten Genabschnitt, der eine einzelkettige Fv-Domäne (scFv) eines spezifischen Antikörpers codiert, und einen zweiten Genabschnitt, der die Transmembran- und cytoplasmatischen, und gegebenenfalls die extrazellulären, Domänen eines Immunzellen stimulierenden Moleküls teilweise oder ganz codiert, das bei Transfektion auf Immunzellen sowohl die scFv-Domäne als auch die Domänen des Immunzellen stimulierenden Moleküls in einer Einzelkette auf der Oberfläche der transfizierten Zellen so exprimiert, dass die transfizierten Zellen zur Aktivierung und/oder Proliferation stimuliert werden und eine nicht beschränkte MHC-Antikörper-Typ-Spezifität besitzen, wenn die exprimierte scFv-Domäne an ihr Antigen bindet.
  2. Chimeres Gen nach Anspruch 1, wobei der zweite Genabschnitt weiterhin die extrazelluläre Domäne des immunzellen stimulierenden Moleküls teilweise oder ganz enthält.
  3. Chimeres Gen nach Anspruch 1 oder 2, wobei der erste Genabschnitt die scFv-Domäne eines Antikörpers gegen Tumorzellen codiert.
  4. Chimeres Gen nach Anspruch 1 oder 2, wobei der erste Genabschnitt die scFv-Domäne eines Antikörpers gegen Virus-infizierte Zellen codiert.
  5. Chimeres Gen nach Anspruch 4, wobei das Virus HIV ist.
  6. Chimeres Gen nach einem der Ansprüche 1 bis 5, wobei das Immunzellen stimulierende Molekül eine Lymphocyten-Rezeptor-Kette, eine Kette des TCR/CD3-Komplexes oder eine Untereinheit eines Fc- oder IL-2-Rezeptors ist.
  7. Chimeres Gen nach einem der Ansprüche 1 bis 6, wobei das Immunzellen stimulierende Molekül eine Lymphocyten-Rezeptor-Kette ist.
  8. Chimeres Gen nach Anspruch 7, wobei die Lymphocyten-Rezeptor-Kette eine Kette eines T-Zell-Rezeptors ist.
  9. Chimeres Gen nach Anspruch 8, wobei die Kette eines T-Zell-Rezeptors die α-, β-, γ- oder δ-Kette eines Antigen-spezifischen T-Zell-Rezeptors ist.
  10. Chimeres Gen nach einem der Ansprüche 1 bis 6, wobei das Immunzellen stimulierende Molekül eine Kette des TCR/CD3-Komplexes ist.
  11. Chimeres Gen nach Anspruch 10, wobei die Kette des TCR/CD3-Komplexes eine Zeta- oder Eta-Isoform-Kette ist.
  12. Chimeres Gen nach einem der Ansprüche 1 bis 6, wobei das Immunzellen stimulierende Molekül eine Untereinheit eines Fc-Rezeptors oder eines IL-2-Rezeptors ist.
  13. Chimeres Gen nach Anspruch 12, wobei die Untereinheit eines Fc-Rezeptors oder eines IL-2-Rezeptors eine gemeinsame Untereinheit von IgE- und IgGbindenden Fc-Rezeptoren ist.
  14. Chimeres Gen nach Anspruch 13, wobei die gemeinsame Untereinheit die Gamma-Kette ist.
  15. Chimeres Gen nach Anspruch 12, wobei die Untereinheit eines Fc-Rezeptors oder eines IL-2-Rezeptors die CD16α-Kette von FcγRIII ist.
  16. Chimeres Gen nach Anspruch 12, wobei die Untereinheit eines Fc-Rezeptors oder eines IL-2-Rezeptors die α- oder β-Untereinheit des IL-2-Rezeptors ist.
  17. Chimeres Gen nach einem der Ansprüche 1 bis 5, wobei das Immunzellen stimulierende Molekül CD2 oder CD28 ist.
  18. Expressionsvektor, umfassend ein chimeres Gen nach einem der Ansprüche 1 bis 17.
  19. Immunzelle, die eine Antikörperspezifität besitzt und mit einem Expressionsvektor nach Anspruch 18 transformiert ist.
  20. Immunzelle, die eine Antikörperspezifität besitzt und ein chimeres Gen nach einem der Ansprüche 1 bis 17 umfasst.
  21. Immunzelle nach Anspruch 19 oder 20, ausgewählt aus der Gruppe bestehend aus einer natürlichen Killerzelle, einer Lymphokin aktivierten Zelle, einer cytotoxischen T-Zelle, einer Helfer-T-Zelle und einer Unterart davon.
  22. Arzneimittel, umfassend das chimere Gen nach einem der Ansprüche 1 bis 17, den Expressionsvektor nach Anspruch 18 und/oder die Immunzelle nach Anspruch 20 oder 21.
  23. Arzneimittel zur Behandlung eines Tumors in einem Patienten, umfassend Lymphocytenzellen des Patienten, die mit einem Expressionsvektor transformiert sind, der ein chimeres Gen nach einem der Ansprüche 1 bis 3 oder 6 bis 17 umfasst, wobei der erste Genabschnitt eine scFv-Domäne eines für die Tumorzellen spezifischen Antikörpers codiert, wobei die transformierten Zellen gegen die Tumorzellen gerichtet sind, um dadurch die Rückbildung des Tumors herbeizuführen.
  24. Arzneimittel zur Behandlung einer viralen Infektion in einem Patienten, umfassend Lymphocytenzellen des Patienten, die mit einem Expressionsvektor transformiert sind, der ein chimeres Gen nach einem der Ansprüche 1, 2 oder 4 bis 17 umfasst, wobei der erste Genabschnitt eine scFv-Domäne eines für die Virus-infizierten Zellen spezifischen Antikörpers codiert, wobei die transformierten Zellen gegen die Virus-infizierten Zellen gerichtet sind, um dadurch eine Verringerung der viralen Infektion herbeizuführen.
  25. Arzneimittel nach Anspruch 23 oder 24, wobei die Lymphocytenzellen periphere Blutzellen sind.
EP93908414A 1992-03-18 1993-03-18 Chimäre rezeptorgene und entsprechend damit transformierte zellen Expired - Lifetime EP0638119B1 (de)

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